Regulatory strategies for early device development and approval.

The development of new technology to treat unmet clinical needs is an important component of modern cardiovascular disease. The need for this has been emphasized in the past several years beginning with the Food and Drug Administration (FDA) guidance document on Early Feasibility Studies in 2012 and then the 21st Century Cures legislation. A number of steps need to be considered in this process by the stakeholders involved including physician innovators and scientists, professional societies such as Society for Cardiovascular Angiography & Interventions, regulatory agencies, and medical device companies. This article focuses on the early iterative steps required to optimize the process and achieve the goal of timely efficient innovation and device development in cardiovascular disease.

Early Feasibility Studies for Cardiovascular Devices in the United States: JACC State-of-the-Art Review.

The development of technology to treat unmet clinical patient needs in the United States has been an important focus for the U.S. Food and Drug Administration and the 2016 Congressional 21st Century Cures Act. In response, a program of early feasibility studies (EFS) has been developed. One of the important issues has been the outmigration of the development and testing of medical devices from the United States. The EFS committee has developed and implemented processes to address issues to develop strategies for early treatment of these patient groups. Initial implementation of the U.S. Food and Drug Administration EFS program has been successful, but residual significant problems have hindered the opportunity to take full advantage of the program. These include delays in gaining Institutional Review Board approval, timeliness of budget and contractual negotiations, and lack of access to and enrollment of study subjects. This paper reviews improvements that have been made to the U.S. EFS ecosystem and outlines potential approaches to address remaining impediments to program success.

Workflow efficiency for the treatment planning process in CT-guided high-dose-rate brachytherapy for cervical cancer.

PURPOSE: To investigate process efficiency, we present a prospective investigation of the treatment planning phase of image-guided brachytherapy (BT) for cervical cancer using a specific checklist. METHODS AND MATERIALS: From October 2012 to January 2014, 76 BT procedures were consecutively performed. Prospective data on the CT-based treatment planning process was collected using a specific checklist which details the following steps: (1) dosimetry planning, (2) physician review start, (3) physician review time, (4) dosimetry processing, (5) physics review start, (6) physics review, and (7) procedural pause. Variables examined included the use of a pre-BT MRI, clinic duty conflicts, resident teaching, and the use of specific BT planners. Analysis was performed using descriptive statistics, t-test, and analysis of variance. RESULTS: Seventy-five prospectively gathered checklists comprised this analysis. The mean time for treatment planning was 95 minutes (med 94, std 18). The mean intervals in the above steps were (1) = 42, (2) = 5, (3) = 19, (4) = 10, (5) = 6, (6) = 13, and (7) = 26 minutes. There was no statistical difference in patients who had a pre-BT MRI. Resident teaching did not influence time, p = 0.17. Treatment planning time was decreased with a specific planner, p = 0.0015. CONCLUSIONS: A skillful team approach is required for treatment planning efficiency in image-guided BT. We have found that the specific BT planners can have a significant effect on the overall planning efficiency. We continue to examine clinical and workflow-related factors that will enhance our safety and workflow process with BT.

Interfraction motion of the vaginal apex during postoperative intensity modulated radiation therapy: are we missing the target?

OBJECTIVE: This study aimed to evaluate changes in vaginal cuff position and rectal distention during whole pelvic intensity modulated radiation therapy using daily image guidance for patients with gynecologic malignancies. MATERIALS AND METHODS: We reviewed 145 daily images from 5 patients treated with intensity modulated radiation therapy after total abdominal hysterectomy for endometrial or cervical cancer. A fiducial marker was placed in the vaginal cuff tissue before computed tomographic simulation. The 2008 ASTRO consensus guidelines for delineation of clinical target volumes were used to deliver 45 to 50 Gy to the target structures. Daily megavoltage computed tomographic images were reviewed and changes in position of the fiducial marker as compared to the initial planning scan were recorded in the anterior-posterior (AP), lateral, and superior-inferior dimensions. Changes in rectal distention were also recorded. The position of the fiducial marker relative to the planning target volumes was reviewed on each daily image. RESULTS: The average shifts of the gold seed in the AP, lateral, and superior-inferior dimensions were 7 mm (range, 0-28 mm), 3 mm (range, 0-7 mm), and 2.9 mm (range, 0-12 mm), respectively. Distention of the rectum ranged from 20.5 to 60.1 mm and correlated with movement of the gold seed in the AP dimension (R = 0.53). For 2 patients, the fiducial marker was within 5 mm of the planning target volume margin on 8/40 treatments, or outside the planning target volume on 4/40 treatments. This did not significantly impact total delivered dose to the planning target volume. CONCLUSIONS: Daily image guidance confirms significant interfraction movement of the vaginal cuff tissue, which may exceed suggested guidelines for clinical target volume margins.

Mycobacterium vaccae induces a population of pulmonary CD11c+ cells with regulatory potential in allergic mice.

The hygiene hypothesis proposes that common, harmless microorganisms, present throughout our evolutionary history, have helped to develop immunoregulatory mechanisms that prevent inappropriate immune responses by the host. Using a mouse model of allergic pulmonary inflammation, we report that treatment with an ubiquitous saprophytic mycobacterium, Mycobacterium vaccae, significantly reduces allergic inflammation by decreasing type 2 responses such as eosinophilia and IL-4 expression. Rather than observing an increase in type-1 cytokine expression, we found elevated production of IL-10 in the lungs suggesting a role for regulatory T cells. Since induction of these cells may be dependent on APC, we investigated the effects of M. vaccae treatment on pulmonary CD11c+ cells. Increased levels of IL-10, TGF-beta and IFN-alpha mRNA were detected in CD11c+ cells from M. vaccae-treated allergic mice. We propose that M. vaccae-induced CD11c+ cells have a potential regulatory role at the site of inflammation through their secretion of immunomodulatory cytokines.